DESCRIPTION (provided by investigator): The Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) study is a large pragmatic multi-center randomized clinical trial designed to evaluate the comparative effectiveness and safety of azithromycin-based extended-spectrum antibiotic prophylaxis (azithromycin plus standard narrow-spectrum cephalosporin) relative to standard single-agent cephalosporin prior to surgical incision to prevent post-cesarean infection. In contrast to cephalosporin, azithromycin is effective against other common pathogens, especially ureaplasma, a strong risk factor for post-cesarean endometritis when present in the chorioamnion, and the most common isolate from wound infections. Our preliminary studies suggest that extended-spectrum prophylaxis may effectively lower the risk of post-cesarean infection compared to standard cephalosporin alone. We will enroll women at high risk for post-cesarean infection despite standard prophylaxis - those undergoing a non-elective cesarean during labor or after membrane rupture. These women face a high likelihood of ascending colonization and infection with ureaplasmas from the lower genital tract. During the 4-year project period, 3 collaborating perinatal centers, recognized nationally for their expertise in the conduct of multi-center clinical trials, will randomize 2000 women undergoing non-elective (unscheduled) cesarean to either 500mg of intravenous azithromycin or identical placebo initiated prior to surgery;concurrently, both groups will also receive standard single-dose cefazolin prophylaxis (or clindamycin if allergic to cephalosporin). Women will be followed for at least 30 days according to CDC recommendations for ascertaining surgical site infections. Neonatal outcomes will also be recorded. The following specific aims will be addressed: Specific aim 1 (Effectiveness): To determine if pre-incision extended-spectrum prophylaxis reduces the risk of post-cesarean infection (endometritis, wound or other infections) compared to standard cephalosporin alone among women undergoing unscheduled cesarean delivery. {Specific aim 2 (Safety): To evaluate the safety of azithromycin-based pre-incision extended spectrum prophylaxis relative to standard cephalosporin prophylaxis in terms of the frequency of adverse composite and individual neonatal and maternal outcomes including suspected or proven neonatal infection, drug reactions or side effects including neonatal pyloric stenosis, and infection with resistant organisms.} {Specific aim 3: To collect and store biological specimens (umbilical cord blood and amniotic fluid) for future studies, primarily to assess the association between prenatal exposure to ureaplasmas and adverse neonatal outcomes (systemic inflammatory response syndrome, sepsis, pneumonia and bronchopulmonary dysplasia and death) and the potential for prenatal azithromycin use to prevent these outcomes.} PUBLIC HEALTH RELEVANCE: We propose a large multi-center randomized trial to evaluate the benefits and safety of an innovative antibiotic prophylaxis strategy at cesarean delivery to reduce the incidence of infection, one of the top 5 causes of pregnancy-related death and illness in the US. The regimen adds a second antibiotic to the standard cephalosporin to extend the spectrum of coverage to other common bacteria especially ureaplasmas. Preliminary data from a single center suggest that this extended-spectrum antibiotic prophylaxis regimen may significantly reduce post-cesarean infections among women undergoing cesarean delivery. The trial will be conducted at 3 Ob/Gyn departments experienced in the conduct of clinical trials: University of Alabama at Birmingham, University of North Carolina, Chapel Hill and University of Texas Medical Branch in Galveston.